DE60127552T2 - INTRAKORPORAL MEDICAMENTS FOR THE HIGH-ENERGETIC PHOTOTHERAPEUTIC TREATMENT OF A DISEASE - Google Patents

Description

CROSS-REFERENCE TO A RELATED REGISTRATION

These Registration is based on the provisional Application USSN 60 / 195,090 and a continuation-in-part application USSN 09 / 216,787 (entitled "High Energy Phototherapeutic Agents "), filed on December 21, 1998, which is hereby incorporated by reference in its entirety is included.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The The present invention relates to certain radiosensitizable drugs and methods of treating human or animal tissue using such drugs in combination with radiotherapy, these radiation-sensitive drugs are radiation-sensitive Means to serve in high-energy phototherapy. The inventors The present invention has found that such medicaments to treat a variety of conditions affecting the skin and related Organs, the mouth and digestive tract and related organs, the urinary and reproductive organs and related organs, the respiratory tract and related organs, the Circulatory system and related organs, the head and neck, the endocrine and lymphoreticular Systems and related organs, various other tissues, such as connective tissue and various tissue surfaces, the while a surgical procedure are exposed, as well as various Tissues presenting a microbial, viral, fungal or parasitic infection exhibit, influence, useful are. These drugs are in different formulations which liquid, semi-solid, solid or aerosol delivery vehicles, and are for intracorporeal administration via different conventional Types and ways, including intravenous Injection (i.v.), intraperitoneal injection (i.p.), intramuscular injection (i.m.), intracranial injection (i.c.), intratumoral injection (i.t.), intraepithelial injection (i.e.), transcutaneous delivery (t.c.) and administration through the esophagus (p.o.). A Irradiation of tissues containing such drugs with Ionizing radiation produces a desired therapeutic response, like destruction a microbial infection, reduction or elimination of Tissue irritation, reduction or elimination of hyperproliferative tissue, Reduction or elimination of cancerous or precancerous tissue, reduction or elimination of surface or sub-surface lipocytes or lipid deposits and many other similar indications.

DESCRIPTION OF THE STATE OF THE TECHNOLOGY

diseased Tissues or tumors, like those of cancer, are often used of high-energy, strongly penetrating ionizing radiation (i.e., ionizing radiation or radiation) in a process, which is known as radiotherapy treated.

conventional Radiotherapy (which typically ionizing radiation with Energies of 1 keV or higher generally works by attacking fast growing Cells with ionizing radiation. The use of such radiation is due to her wealth, penetrate deeply into tissue, attractive, especially when sick Tissue of bone or other dense or opaque structures be or is located in it. Unfortunately, that restricts Using fast growth as the only target criterion not the effects of such treatment on diseased tissue and as a result, healthy tissue is often destroyed or damaged.

When As a result, some improvements were made to the procedures Delivered the radiation to the disease site, so the Effects of such radiation on the general area of the restricted tissue. However, since healthy tissue and diseased tissue are typically similar biological response to ionizing radiation, consists Need to improve the effectiveness (or biological response on) the emitted radiation within the environment of the diseased Tissue to the diseased tissue, so as not the surrounding healthy To influence tissue.

Accordingly, some researchers have focused their efforts on the development of agents that are activated by or increase the therapeutic potential of such ionizing radiation. Such agents are known as radiation-sensitizing agents and, when used in combination with ionizing radiation, represent a therapeutic application which is considered high-end ergetic phototherapy is known. As radiation sensitizing agents act by absorbing or otherwise interacting with penetrating ionizing radiation and locally converting that radiation to a more biologically active form, it is desirable that such radiation sensitizing agents exhibit high intrinsic radiosensitivity and preferential concentration in diseased tissue (thus allowing maximum, selective delivery of the therapeutic effects of such radiation to such diseased tissue containing such agent).

by virtue of the central nature of many diseases, it is desirable this preferred concentration of radiation-sensitizing By means of natural operations or over to achieve localized administration of the agent. The desired result is then that the radiation becomes more effective, if that for radiation Sensitizing agent is present in the tissue, so less radiation is needed to the lesion, to treat the tumor or other diseased tissue, and accordingly becomes potential Damage to surrounding healthy tissue, which consists of collateral Exposure of the radiation results, decreases. Consequently, the Safety and effectiveness are improved if one has means which at a preferred concentration in diseased tissue in are able.

Of the final The success or failure of high-energy phototherapy therefore depends from: (1) the therapeutic performance of the radiation sensitizer Means and (2) disease specificity at giving of means in place of the disease or diseased tissue. Currently However, funds used and targeted procedures showed in each of these categories unacceptable results.

The therapeutic achievement of a for Radiation-sensitizing agent is a function of increased Absorption of applied radiation dose in sensitized Tissues relative to non-sensitized tissues. These Different absorption is generally by use of radiation-sensitive agents with a high absorption cross section for one special type of radiation (such as X-rays) causes. To the For example, metal or halogen atoms are often used, either in atomic form or incorporated into a molecular carrier, due to its high X-ray cross section. The absorption of X-rays by such radiotensible materials seems to secondary radiation emissions, Ionization and other chemical or physical processes lead, which the localized cytotoxicity of the applied energy (i.e., that caused by radiation) Increase cell death or "light cytotoxicity").

however is a high light cytotoxicity not enough to make a remedy acceptable. The Means must also be a negligible Have effect when no energy is applied (i.e. have low toxicity in the absence of radiation or "dark cytotoxicity"). Unfortunately are many agents currently considered to be radiation sensitive Be investigated, unfavorable, since they either (a) one relatively high dark cytotoxicity or (b) a low ratio of light cytotoxicity to dark cytotoxicity which limits their effectiveness and tolerability. On the other hand are means with a high ratio from light-to-dark cytotoxicity desirable, since they are (1) over a range of dosages can be safely used, (2) have improved efficacy at the treatment site (due to compatibility with use at higher dosages as a consequence of their relative safety) and (3) everywhere in the world body better tolerated by the patient.

An additional problem with many current radiation-sensitive agents is that the agent does not achieve a significant preferred concentration in diseased tissue. Specifically, most targeting of radiation sensitizing agents has been based on physical targeting, such as diffusion through tumors through permeable newly formed vessels, which ultimately, based on the permeability of the tumor to agents that are water soluble or present in a suspension formulation, is successful or not is successful. As a result, typically, high doses of the agent must be administered, either locally or systemically, so as to saturate all tissues in the hope of achieving a therapeutic level in the desired treatment area or target. After such administration of an agent, a patient must wait for a clearance time of hours to days to hopefully allow excess agent to be eliminated from the healthy tissues surrounding the desired treatment site. Thereafter, irradiation of the residual agent at the treatment site will hopefully produce the desired therapeutic effect in the diseased tissue. Unfortunately, this approach may also damage healthy surrounding tissue by undesired activation of the residual agent still present in the healthy surrounding tissue. One approach to solving this problem is the radiation sensitizing agent with an On couple, which is capable of providing improved biological targeting to the diseased tissue. However, it turned out to be very difficult to achieve.

It would be too highly desirable, if that for Radiation sensitive agents for improving identification of target size, location and depth could be used so that the therapeutic radiation is more accurate to the target, how to a cancerous one Tumor, could be delivered. Furthermore, would a combined diagnostic use (as a contrast agent) and therapeutic use (as a radiation-sensitizing Means) of the agent the risk for reduce the patient by (1) reducing the number of required Procedures for Diagnosis and treatment are necessary, (2) Reducing the overall diagnosis and treatment time and (3) reducing costs.

So made the inherent Disadvantages of different current radiation sensitive Agents and medicaments containing such agents, a compatible radiation therapy for different human and animal conditions difficult or impossible.

Therefore It is an object of the present invention to provide new intracorporeal Radiation-sensitive drugs, medical uses for such Drugs based on improved specificity of such Medicines for the wished Tissue being treated and methods of treatment Use of such drugs to provide, this in an elevated Efficacy and safety and reduced costs of treatment results.

WO-A-99/45869 discloses an enzyme orthokeratology method for correcting Refractive errors in the eye of a mammalian recipient. One Accelerating a reshaping of the cornea is by administering a cornea-curing Amount of a cornea-curing In the eye of a recipient reached. The reformation is under the influence of a hard Contact lens or a series of lenses with a concave curvature, which correct a refractive error. The usage of UV light is used to induce oxidative crosslinking in Combination with a photosensitizing agent into consideration drawn.

The The present invention relates to novel intracorporeal radiation-sensitive Medicines and certain medical uses of such Drugs and methods of treatment using such Medicines for the treatment of human or animal tissue, being a primary one Active ingredient of such drugs a halogenated xanthene or a halogenated xanthene derivative, and more preferably Rose Bengal or a functional derivative of Rose Bengal.

The The present invention provides a medicament for intracorporeal Ready for administration, wherein the medicament is at least one halogenated Xanthene as a primary Active ingredient in aqueous solution wherein the halogenated xanthene in a concentration of higher than 0.001% to less than 20% and where the drug for use in high energy phototherapeutic treatment of human and animal tissue, using of applied ionizing radiation with an energy of more as 1 KeV and less than 1000 MeV.

The halogenated xanthenes represent a family of effective for radiation Sensitizing agents, which by irradiation of the treatment site with ionizing radiation, such as X-rays, activated become. Such drugs are for intracorporeal administration suitable and are therefore intracorporeal drugs. Such drugs can are also called drugs or drugs.

In a preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting the skin and related Organs influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting the mouth and digestive tract and related organs influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting urinary tract and reproductive organs and related organs.

In another preferred embodiment, such drugs become highly energetic phototherapeutic treatment of a variety of conditions affecting the respiratory tract and related organs.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting the circulatory system and related organs influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting the head and neck influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions affecting the endocrine and lymphoreticular Systems and related organs influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treating a variety of states, which are various others Tissues, such as connective tissue and various tissue surfaces, which while a surgical procedure are exposed, influence, used.

In another preferred embodiment Such drugs become high-energy phototherapeutic Treatment of a variety of conditions associated with microbial or more parasitic Infection are used.

In another preferred embodiment such drugs are available in different formulations, including liquid, semi-solid, solid or aerosol delivery vehicles, as well as in tablet, capsule, suppository and other similar Molds made.

BRIEF DESCRIPTION OF THE DRAWINGS

at the description of the preferred embodiments is made to the attached drawings Referenced, wherein:

1 (a) shows the generalized chemical structure of the halogenated xanthenes.

1 (b) shows the chemical structure of Rose Bengal.

2 is a graph of energy versus X-ray cross section for halogens.

DETAILED DESCRIPTION THE PRESENTLY PREFERRED EMBODIMENTS

The The present invention relates to new radiosensitive medicaments and certain medical uses of such radiosensitivity Drugs and procedures for high-energy phototherapeutic Treatment using such drugs for treatment of human or animal tissue, being a primary agent of such drugs a halogenated xanthene or halogenated Is xanthene derivative. The inventors of the present invention have discovered that such halogenated xanthenes, as described in more detail below discussed will, desirable have high-energy phototherapeutic effects, when they are administered to certain human or animal tissues or be given elsewhere. The desirable effects include decreasing or eliminating the disease or diseased tissue or of other undesirable States, including the complete Elimination of cancerous or precancerous tumors and infectious agents, and they are in a variety of conditions affecting the skin and related Organs, the mouth and digestive tract and related organs, the urinary tract and reproductive organs and related organs, the respiratory tract and related organs, the circulatory system and related organs, the head and neck, the endocrine and lymphoreticular systems and related organs, various other tissues, such as tissue, the while a surgical procedure are exposed, as well as various Tissues that cause microbial, viral, fungal or parasitic infection have, influence, usable.

In a preferred embodiment, such drugs are in various formulations suitable for intracorporeal administration, including in various liquid, semisolid th, solid or aerosol delivery vehicles, as well as in tablet, capsule, suppository and other similar forms. Such drug formulations are suitable for delivery by various conventional manners and routes (hereinafter defined as intracorporeal administration), including, but not limited to, intravenous injection (iv), intraperitoneal injection (ip), intramuscular injection (im), intracranial injection (ic ), intratumoral injection (it), intraepithelial injection (ie), transcutaneous delivery (tc) and administration through the esophagus (po); additional modes and routes of administration include intra-abdominal, intra-apendicular, intra-arterial, intra-articular, intrabronchial, intrabuccal, intracapsular, intracardiac, intra-cartilaginous, intracavitary, intracetal, intracranial, intracutaneous, intracystic, intradermal, intraductal, intraduodenal, intrafascicular, intrafett, intrafibrillar, intrafissural, intragastric , intraglandular, intrahepatic, intraintestinal, intralamellar, intralesional, intraligamentous, intralingual, breast, intramedullary, intrameningeal, intramyocardial, intranasal, intraocular, intraoperative, intraoral, intraosseous, ovarian, pancreatic, intraparietal, intraparietal, intrapelvine, intrapericardial, intraperineal, intraperitoneal, placental, intrapleural, intrapontine, prostate, intrapulmonary V administration, administration to the spleen, intrasternal, intrastromal, intrasynovial, intratarsal, intratesticular, intrathoracic, intratonsillar, intratracheal, intratubal, intratympanic, intraureteric, intraurethral Administration, administration to the uterus, intravaginal, intravascular, intraventricular, intravertebral, intravesical or intravitrous administration. Such drugs are thus referred to as intracorporeal drugs (ie, drugs suitable for intracorporeal administration).

1. Properties of the preferred radiosensitive Components and drug formulations.

The inventors of the present invention have discovered a class of radiosensitizers which can be used in a very extensive manner for the preparation of intracorporeal drugs for the high-energy phototherapeutic treatment of a disease in certain human and animal tissues. These radiosensitizers are termed halogenated xanthenes and are known in the art 1a in which the symbols X, Y and Z represent various elements present at the indicated positions and the symbols R ¹ and R ^{2 represent} various functions existing at the indicated positions. The halogen content of the halogenated xanthenes makes this class of agents highly effective absorbents of X-rays or other ionizing radiation having an energy greater than about 1 keV and less than about 1000 MeV, and thus as radiosensitive components in various radiation sensitizing drugs. which are used in conjunction with such radiation in high-energy phototherapy suitable.

Selected chemical and physical properties (such as chemical entities at positions X, Y and Z and functions R ¹ and R ² , together with the molecular weight) of representative halogenated xanthenes are summarized in attached Table 1 (below). Certain general features of this class of agents are described in greater detail in USSN 09 / 130,041, filed August 6, 1998 (entitled "Improved Method for Targeted Treatment of Disease"), USSN 09 / 184,388, filed November 2, 1998 (assigned to the Title "Method for Improving Imaging and Photodynamic Therapy"); USSN 09 / 216,787 filed December 21, 1998 (entitled "High Energy Phototherapeutic Agents") and USSN 60 / 149,015 filed Aug. 13, 1999 (entitled "Improved Topical Medicaments and Methods for Photodynamic Treatment of Disease"). ), each of which is incorporated herein by reference in its entirety. In general, the halogenated xanthenes are rapidly eliminated from the body by a large radiation absorbance cross section, low dark cytotoxicity (toxicity to cells or tissues in the absence of radiation), high light cytotoxicity (toxicity to cells or tissues by irradiation), relatively low cost, a capability and characterizes chemical properties and properties of radiation-sensitizing agents that are substantially unaffected by the local chemical environment or by attachment of functional derivatives at positions R ¹ and R ² . The halogenated xanthenes also have a preference for concentration in diseased tissue, and thus are able to have an increased dose-rate improvement compared to what was possible with previously known agents. These particular properties of the halogenated xanthenes, and particularly the intracorporeal drugs formulated from such agents, make such agents and medicaments excellent for high energy phototherapeutic treatment of a disease in human and animal tissues.

The intracorporeal drug according to the present invention comprises at least one halo xanthene at a concentration of greater than about 0.001% and less than about 20%, including, for example, one or more of: 4 ', 5'-dichlorofluorescein; 2 ', 7'-dichlorofluorescein;4,5,6,7-tetrachloro; 2 '4', 5 ', 7'-tetrachlorofluorescein;Dibromofluorescein; Solvent Red 72; Diiodfluorescein; Eosin B; Eosin Y; ethyleosin; Erythrosine B; Phloxin B; Rose Bengal (4,5,6,7-tetrachloro-2 ', 4', 5 ', 7'-tetraiodofluorescein; 1b ); 4,5,6,7-Tetrabromoerythrosin; Mono-, di- or tribromerythrosine; Mono-, di- or trichloroerythrosine; Mono-, di- or trifluoroerythrosine; 2 ', 7'-dichloro-4,5,6,7-tetrafluorfluorescein; 2 ', 4,5,6,7,7'-hexafluorofluorescein and 4,5,6,7-tetrafluorofluorescein. Since the radiation cross section of halogens increases substantially in the order F <Cl <Br <I (as in FIG 2 Further, it is preferred that this drug include as a radiosensitive component those halogenated xanthenes having a high content of I or Br. As shown in Table 1 (below), tetrabromerythrosine, Rose Bengal, Phloxin B, Erythrosin B and Eosin Y have high levels of I or Br relative to other halogenated xanthenes, and are more potent for use as a radiosensitive component in such drugs prefers. Further, the high iodine content of Rose Bengal and its derivatives and the additional bromine substitution of 4,5,6,7-tetrabromerythrosine and its derivatives make these agents more preferred for use as a radiosensitive ingredient in such medicaments.

The Inventors of the present invention have found that intracorporeal Medications that act as a radiosensitive component at least contain a halogenated xanthene, a preferred accumulation of the radiosensitive constituent in diseased tissue. Such an accumulation of the radiosensitive constituent in or in physical proximity increased to such a tissue the effectiveness of for Radiation sensitization of such a tissue (i.e., conversion of applied ionizing radiation in localized cytotoxic Effects in or near such tissue). It is believed that this increase in yield from the increased probability that immediately released energy (i.e., scattered or otherwise re-emitted energy, which by interaction of applied Ionizing radiation with the for Radiation-sensitizing agent is released) advantageously with interacts with the target tissue (before annihilating or otherwise Dissipation in an ineffective manner), whenever the radiosensitive Component, which for such released energy is as near as possible possible is concentrated on such a target tissue results. In simple In words, the released energy, which is generally a short middle one has a free path, has a higher Probability of interacting with the target tissue if they is released from a radiosensitive constituent, which at a location, in or near the target tissue.

For example, it is possible to estimate the potential of a tissue accumulation agent based on the distribution coefficient K _p . It is generally claimed that this in vitro parameter has a predictive value for the in vivo delivery of the agent at the cellular level. In particular, a value greater than one is believed to exhibit agents capable of and being capable of localization in tumor or other diseased tissue, and more particularly in plasma membranes of cells constructed from such tissue are to have enhanced therapeutic efficacy in such tissue. K _p is determined by measuring the ratio of the equilibrium concentrations of an agent in a lipophilic phase (n-octanol) which is in contact with an aqueous phase (saline). Comparative values of K _p are shown in Table 2 (below). The high K _p values for the halogenated xanthenes indicate that the halogenated xanthenes will have a tendency to accumulate in tumor or other diseased tissue and should be capable of exhibiting excellent high energy phototherapeutic efficacy in such tissue ,

A specific example of such preferred accumulation and therapeutic response of the halogenated xanthenes in diseased tissue is shown by Rose Bengal. In particular, the inventors of the present invention have found that Rose Bengal accumulates preferentially in (ie targeting) some tumors and other diseased tissues. This preference for diseased tissue accumulation is shown by the following examples with which we intend to illustrate and not limit the present invention:
Initially, tumor cell suspensions (eg, melanoma, breast tumor, liver tumor, renal carcinoma, gallbladder tumor, or prostate tumor) were injected subcutaneously into the flanks of nude mice, resulting in the formation of primary tumors with a tumor volume of about 0.5 to 1 cm ³ within a few Weeks at the injection site resulted.

Thereafter, a solution of Rose Bengal (for example, ≤100 μl of 10% Rose Bengal in saline) was intratumorally injected followed by therapeutic irradiation of the tumor within several hours of administration using X-rays (for example, 10 Gy at 120 keV) or Gam mastblasting (for example 4 to 10 Gy at 1.02 MeV). This resulted in selective destruction of the tumor tissue without significant effect on healthy surrounding tissue.

Additionally discovered the inventors of the present invention that an intratumoral Injection (i.t.) of different Rose Bengal formulations in the other tumor models (i.e., breast tumor, liver tumor, renal carcinoma, gallbladder tumor or prostate tumor) in a similar resistant Accumulation of Rose Bengal everywhere in tumor volume, with more than 75% of the injected Rose Bengal dose remained in the tumor after several weeks. A peritumoral injection (i.e., an injection into normal tissue around the outer edges of the Tumor) showed no such resistance in normal tissue, with less than 1% of Rose Bengal in the Surrounding the tumor remained after 24 hours.

So the inventors of the present invention have shown that medicaments, which at least one halogenated xanthene and especially rose Bengal contain a considerable Preference for an accumulation in tumor or other diseased tissue via intracorporeal Have administration and that the medication when in one such tissue as effective, highly tissue-specific for radiation Sensitizing agents can be used.

In addition to excellent fitness for direct administration into desired tissue which is treated Being, like a tumor of interest, is the virtue of the halogenated Xanthene for accumulation in certain tissues a basis for a high selective, systemic delivery of the halogenated xanthenes ready in such tissues. For example, the relatively high distribution coefficient shows from Rose Bengal a preference for an accumulation in lipophilic tissue, such as cutaneous lipocytes. The Inventors of the present invention have found that a systemic Administration of Rose Bengal, for example as an aqueous solution, which administered by intraperitoneal injection (i.p.) or by the esophagus (p.o.) becomes, in a highly selective accumulation of the means in certain Tissues, as in the cutaneous fat deposits of obese laboratory mice. Histological examination of skin samples from such animals shows that the accumulated agent is essentially due to cutaneous lipocytes limited is. About that In addition, activation of this accumulated agent provides a selective destruction of such lipocytes, with no effect on overlying skin or underneath lying muscle tissue.

Moreover, the inventors of the present invention have discovered that the means by which the halogenated xanthenes are targeted to the particular tissues or other sites can be further optimized by adding specific functional derivatives at positions R ¹ and R ² , as follows to alter the chemical distribution or biological activity of the agent. For example, attachment of a targeting moiety, or of several at positions R ¹ or R ^2, to improve targeting to particular tissues, such as cancerous tumor tissues or sites of localized infection may be used. An example of this is esterification at the R ¹ position with a short aliphatic alcohol, such as ethanol or n-hexanol, to produce a derivatized agent which exhibits improved distribution into lipid-rich tumor tissues.

It is thus another embodiment of the present invention to include a targeting moiety in at least one of the at least one halogenated xanthene agents, such targeting moiety being selected from the group consisting of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), amino acids, proteins , Antibodies, ligands, haptens, carbohydrate receptors, carbohydrate complexing agents, lipid receptors, lipid complexing agents, protein receptors, protein complexing agents, chelating agents, encapsulating vehicles, short chain aliphatic hydrocarbons, long chain aliphatic hydrocarbons, aromatic hydrocarbons, aldehydes, ketones , Alcohols, esters, amides, amines, nitriles, azides, hydrophilic moieties and hydrophobic moieties. Another example of this embodiment is derivatization of Rose Bengal with a lipid (at position R ^1, via esterification), so as to increase the lipophilicity of Rose Bengal, and thereby modify its targeting properties in directing a patient. An additional further example of this embodiment is derivatization of Rose Bengal with folate (at position R ^1, via esterification or other types of attaching), so the selective targeting of cancer and other cells having an increased Folatrezeptoraktivität or folate metabolism, to increase.

As another example of the desirable chemical, biochemical and physical properties of the halogenated xanthenes and halogenated xanthene derivatives, the present inventors have shown that such agents have a significant combination of low dark cytotoxicity and high light cytotoxicity. This is evidenced by the following results: intracorporeal administration of a drug containing Rose Bengal to tumor bearing laboratory animals at levels; which are equivalent to or higher than 100 mg / kg, resulted in negligible biological effects in the absence of radiation; however, irradiation of tumor tissue in such animals after such administration resulted in significant destruction of such tumor tissue. As described above, the inventors of the present invention have further shown that such agents can be easily eliminated from healthy tissues within several hours, and are known to be rapidly excreted in bile, urine and stool without those healthy tissues damage while they are there. This is in stark contrast to many conventional radiosensitizers, some of which have half lives in healthy tissues on the order of many weeks.

Further Examples of desirable Properties of halogenated xanthenes and halogenated xanthene derivatives are as follows: the halogenated xanthenes and halogenated xanthene derivatives be easy using simple synthetic methods synthesized at low cost, can be easily cleaned and have excellent stability (such as a long shelf life without a need for cooling or an inert atmosphere).

There the halogenated xanthenes and their derivatives are generally fine solid powders are in their pure form, it is preferred that suitable Delivery to desired Tissue such agents are formulated in suitable delivery vehicles. Procedures for such a formulation will be known to those skilled in the art in general. Specifically, such formulations are preferred so as to control delivery of the agent in the body and subsequently contacting and providing desired Tissues that are treated to allow.

It is thus another embodiment of the present invention that at least one halogenated xanthene or halogenated xanthene derivative as an intracorporeal drug is formulated in a form which is suitable for intracorporeal administration via various conventional Types and ways is suitable. Such suitable forms include drugs one, which in a liquid, semi-solid, solid or aerosol delivery vehicles, including aqueous suspensions, non-aqueous Suspensions, solutions, Creams, ointments, gels, syrups, microp drops, suppositories, Tablets and capsules. The at least one halogenated xanthene or halogenated xanthene derivative may be present in such a delivery vehicle solved or be suspended, this vehicle in addition to the at least one halogenated xanthene or halogenated xanthene derivative different Builders, Stabilizers, emulsifiers or dispersants, preservatives, Buffers, electrolytes and tissue penetrating or tissue softening agents lock in can. Such components of the delivery vehicle may be considered the main component (based on the weight or volume) of the drug or be present as a minor component, which in the delivery of the By means of serving in a roll as an additive, without adverse Effect on the tissue or treatment outcome.

To the Close example suitable builders Cellulose and cellulose derivatives such as starch, and alginates.

Examples of suitable stabilizers, emulsifiers or dispersants shut down Liposomes, nanoparticles and nanodispersions, microparticles and microdispersions as well as various lipids, detergents and other surfactants Substances.

Examples suitable preservatives include benzalkonium chloride, thimerosal, quaternary Amines and urea.

Examples Close suitable buffers monobasic or dibasic phosphate salts, citrate salts, bicarbonate salts and ethanolamine.

Examples suitable electrolytes include sodium, potassium, calcium and magnesium chlorides, phosphates and nitrates.

• • verschiedene Sulfoxide, wie DMSO und Decylmethylsulfoxid;
• • verschiedene aliphatische und fette Alkohole, wie Ethanol, Propanol, Hexanol, Octanol, Benzylalkohol, Decylalkohol, Laurylalkohol und Stearylalkohol;
• • verschiedene lineare und verzweigte, gesättigte und ungesättigte Fettsäuren, wie Laurinsäure, Capronsäure, Caprinsäure, Myristinsäure, Stearinsäure, Ölsäure, Isovaleriansäure, Neopentansäure, Trimethylhexansäure, Neodecansäure und Isostearinsäure;
• • verschiedene aliphatische und Alkylfettsäureester, wie Isopropyl-n-butyrat, Isopropyl-n-hexanoat, Isopropyl-n-decanoat, Isopropylmyristat, Isopropylpalmitat, Octyldodecylmyristat, Ethylacetat, Butylacetat, Methylacetat, Methylvalerat, Methylpropionat, Diethylsebacat und Ethyloleat;
• • verschiedene Polyole, wie Propylenglycol, Polyethylenglycol, Ethylenglycol, Diethylenglycol, Triethylenglycol, Dipropylenglycol, Glycerol, Propandiol, Butandiol, Pentandiol und Hexantriol;
• • verschiedene Amide, wie Harnstoff, Dimethylacetamid, Diethyltoluamid, Dimethylformamid, Dimethyloctamid, Dimethyldecamid; bioabbaubarer cyclischer Harnstoff, wie 1-Alkyl-4-imidazolin-2-on; Pyrrolidonderivate, wie 1-Methyl-2-pyrrolidon, 2-Pyrrolidon, 1-Lauryl-2-pyrrolidon, 1-Methyl-4-carboxy-2-pyrrolidon, 1-Hexyl-4-carboxy-2-pyrrolidon, 1-Lauryl-4-carboxy-2-pyrrolidon, 1-Methyl-4-methoxycarbonyl-2-pyrrolidon, 1-Methyl-4-methoxycarbonyl-2-pyrrolidon, 1-Lauryl-4-methoxycarbonyl-2-pyrrolidon, N-Cyclohexylpyrrolidon, N-Dimethylaminopropylpyrrolidon, N-Cocoalkypyrrolidon, N-Tallowalkylpyrrolidon; bioabbaubare Pyrrolidonderivate, wie Fettsäureester von N-(2-Hydroxyethyl)-2-pyrrolidon; cyclische Amide, wie 1-Dodecylazacycloheptan-2-on (Azone^®), 1-Geranylazacycloheptan-2-on, 1-Farnesylazacycloheptan-2-on, 1-Geranylgeranylazacycloheptan-2-on, 1-(3,7-Dimethyloctyl)azacycloheptan-2-on, 1-(3,7,11-Trimethydodecyl)azacycloheptan-2-on, 1-Geranylazacyclohexan-2-on, 1-Geranylazacyclopentan-2,5-dion, 1-Farnesylazacyclopentan-2-on; Hexamethylenlauramid und seine Derivate; und Diethanolamin und Triethanolamin;
• • verschiedene grenzflächenaktive Stoffe, wie anionische grenzflächenaktive Stoffe, einschließlich Natriumlaurat und Natriumlaurylsulfat; kationische grenzflächenaktive Stoffe, einschließlich Cetyltrimethylammoniumbromid, Tetradecyltrimethylammoniumbromid, Benzalkoniumchlorid, Octadecyltrimethylammoniumchlorid, Cetylpyridiniumchlorid, Dodecyltrimethylammoniumchlorid, Hexadecyltrimethylammoniumchlorid; nicht-ionische grenzflächenaktive Stoffe, wie Polaxamer (231, 182, 184), Brij (30, 93, 96, 99), Span (20, 40, 60, 80, 85), Tween (20, 40, 60, 80), Myrj (45, 51, 52), Miglyol 840; verschiedene Salze der Gallensäure, wie Natriumcholat, Natriumsalze der Taurochol-, Glychol-, Desoxycholsäuren; Lecithin;
• • verschiedene Terpene, einschließlich Kohlenwasserstoffe, wie D-Limonen, α-Pinen, β-Caren; verschiedene Terpenalkohole, einschließlich α-Terpineol, Terpinen-4-ol, Carvol; verschiedene Terpenketone, einschließlich Carvon, Pulegon, Piperiton, Menthon; verschiedene Terpen oxide, einschließlich Cyclohexanoxid, Limonenoxid, α-Pinenoxid, Cyclopentenoxid, 1,8-Cineol; verschiedene Terpenöle, einschließlich Ylang ylang, Anis, Chenopodium, Eukalyptus;
• • verschiedene Alkanone, wie N-Heptan, N-Octan, N-Nonan, N-Decan, N-Undecan, N-Dodecan, N-Tridecan, N-Tetradecan, N-Hexadecan;
• • verschiedene organische Säuren, wie Salicylsäure und Salicylite (einschließlich ihre Methyl-, Ethyl- und Propylglycolderivate), Zitronen- und Bernsteinsäure.

Examples of suitable tissue-penetrating, emollient or solvating agents and adjuvants include:

• Various sulfoxides such as DMSO and decylmethyl sulfoxide;
• Various aliphatic and fatty alcohols, such as ethanol, propanol, hexanol, octanol, benzyl alcohol, decyl alcohol, lauryl alcohol and stearyl alcohol;
• Various linear and branched, saturated and unsaturated fatty acids, such as lauric acid, capron acid, capric, myristic, stearic, oleic, isovaleric, neopentanoic, trimethylhexanoic, neodecanoic and isostearic acids;
• Various aliphatic and alkyl fatty acid esters such as isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate, octyl dodecyl myristate, ethyl acetate, butyl acetate, methyl acetate, methyl valerate, methyl propionate, diethyl sebacate and ethyl oleate;
• Various polyols such as propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, glycerol, propanediol, butanediol, pentanediol and hexanetriol;
• Various amides, such as urea, dimethylacetamide, diethyltoluamide, dimethylformamide, dimethyloctamide, dimethyldecamide; biodegradable cyclic urea such as 1-alkyl-4-imidazolin-2-one; Pyrrolidone derivatives such as 1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone, 1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone, 1-lauryl 4-carboxy-2-pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone, N Dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone, N-tallowalkylpyrrolidone; biodegradable pyrrolidone derivatives such as fatty acid esters of N- (2-hydroxyethyl) -2-pyrrolidone; cyclic amides such as 1-dodecylazacycloheptan-2-one (Azone ^®), 1-Geranylazacycloheptan-2-one, 1-Farnesylazacycloheptan-2-one, 1-Geranylgeranylazacycloheptan-2-one, 1- (3,7-dimethyloctyl) azacycloheptan -2-one, 1- (3,7,11-trimethydodecyl) azacycloheptan-2-one, 1-geranylazacyclohexan-2-one, 1-geranylazacyclopentane-2,5-dione, 1-farnesylazacyclopentan-2-one; Hexamethylene lauramide and its derivatives; and diethanolamine and triethanolamine;
• Various surfactants, such as anionic surfactants, including sodium laurate and sodium lauryl sulfate; cationic surfactants, including cetyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride; non-ionic surfactants such as Polaxamer (231, 182, 184), Brij (30, 93, 96, 99), Span (20, 40, 60, 80, 85), Tween (20, 40, 60, 80) , Myrj (45, 51, 52), Miglyol 840; various salts of bile acid, such as sodium cholate, sodium salts of taurocholic, glycholic, deoxycholic acids; lecithin;
• Various terpenes, including hydrocarbons such as D-limonene, α-pinene, β-carene; various terpene alcohols, including α-terpineol, terpinene-4-ol, carvol; various terpene ketones, including carvone, pulegone, piperitone, menthone; various terpene oxides, including cyclohexane oxide, limonene oxide, α-pinene oxide, cyclopentene oxide, 1,8-cineole; various terpene oils, including ylang ylang, anise, chenopodium, eucalyptus;
• Various alkanes, such as N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane, N-tetradecane, N-hexadecane;
• Various organic acids such as salicylic acid and salicylites (including their methyl, ethyl and propyl glycol derivatives), citric and succinic acids.

The The present invention is not limited to the examples given above limited, There are other formulations that are familiar to those skilled in the art, including various simple or complex combinations of vehicles and additives, to improve the delivery of the radiosensitive component of the Drug useful to the target tissues and are included within the present invention to be viewed as.

2. Procedure and medical use of the first-time drug for high-energy phototherapeutic treatment of conditions affecting the skin and related Influence organs.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which affect the skin and related organs of humans and animals, can be used. The drug can be prepared using conventional intracorporeal modes of administration directly or indirectly in, or substantially in the vicinity of, tissues, which are treated, including those of the skin, nails and Scalp, administered. Provide such modes of administration direct delivery of the drug, in or substantially near of tissues being treated or systemic delivery of the drug, in or substantially near tissues, which are treated, ready.

Example indications include treatment for: psoriasis and psoriasis pustulosa; Reiter's syndrome; Skin ulcers, including dermatitis statica, venous ulcers, ischemic ulcers, sickle cell foot ulcers, diabetic ulcers, inflammatory ulcers; Eczema and eczema reaction; various ichthyoses; Atopic dermatitis; Surface wrinkles; Fat reduction near the surface; benign and malignant proliferative disorders, such as benign epithelial tumors and hamartomas; premalignant and malignant epithelial tumors, including actinic keratosis, basal cell carcinoma, squamous cell carcinoma and kerato Akanthom; benign and malignant adnexal tumors; Tumors of pigment-producing cells, including malignant melanoma, solar lentigines, birthmarks and café au lait spots; sarcomas; lymphoma; metastatic tumors, such as metastases of melanoma, breast or other tumors on the skin or related organs; Vascular disorders, such as hemangiomas and fire pain; microbial infection such as bacterial, fungal, yeast, parasitic or other infections; Warts and acne. These examples are provided for illustrative purposes, as the present invention is not limited to the examples given and includes other indications known to those skilled in the art.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice which are radiation resistant have cutaneous melanoma tumors, followed by irradiation of such Tumors with x-rays, gamma rays or other ionizing radiation, to an essential or complete Highly energetic phototherapeutic elimination of such tumors leads. However, the present invention is not preferred to these embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as here described, similar Uses for the specific indications described here and for different ones other similar ones Including indications those which are a therapeutic or cosmetic treatment of Affecting skin and related organs of humans and animals, and are included within the present invention.

3. Procedures and medical use of the first-time drug for high-energy phototherapeutic treatment of conditions affecting the mouth and digestive tract and related organs influence.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which the mouth and digestive tract and related organs of humans and animals can be used. The drug can be under Use of conventional intracorporeal Modes of administration directly or indirectly in, or substantially near of tissues being treated, including those of the mouth, the Gums, tongue, larynx, pharynx, esophagus, Stomach, intestines and intestines. Such Modes of administration provide a direct delivery of the drug at, in or substantially near tissues that are being treated or systemic delivery of the drug, in or essentially nearby of tissues being treated ready.

example indications shut down a treatment for: benign esophageal lesions, Barrett's esophagus or another esophageal hyperplasia and dysplasia and esophageal cancer, including Squamous cell carcinoma, adenocarcinoma, carinosarcoma, pseudosarcoma and sarcoma; Stomach ulcers, Leiomyomas, polyps, neoplasms, lymphoma and pseudolymphoma, adenocarcinoma, primary Lymphoma, leiomyosarcoma; Oral and oropharyngeal cancer and pre-malignancies, ulceration and inflammatory lesions including Squamous cell carcinoma, lymphoma, actinic lip inflammation, nicotine stomatitis, Leukoplakia, erythroplakia; Gum and other peridontal disease, including gingivitis; Laryngeal hyperplasia, dysplasia and neoplasms; colorectal cancer, hyperplasia, dysplasia and polyps; and metastatic tumors, like Metastases of melanoma, breast or other tumors on tissues of the Mouth and digestive tract and related organs. These examples be for illustrative purposes, since the present invention is not limited to the examples given and other indications, which the specialist knows, includes.

In one example of a preferred embodiment of this method of treatment or medical use, the inventors have found that intratumoural injection of a drug solution containing Rose Bengal at a concentration of about 1 to 10% w / v into mice and other animals containing tumors of various types Having such types followed by exposure of such tumors to X-rays, gamma rays or other ionizing radiation results in substantial or complete high energy phototherapeutic destruction of the tumors in the treated area. However, the present invention is not limited to this preferred embodiment, since other medicaments disclosed herein may also be used. Further, other formulations of the halogenated xanthenes as described herein have similar uses for the particular indications described herein and for various other similar indications, including those involving a therapeutic or cosmetic treatment of the mouth and digestive tract and related organs of humans and animals, and are included within the scope of the present invention.

4. Procedures and medical use of the recipient's drug for high-energy Phototherapeutic treatment of conditions which the urinary tract and Reproductive organs and related organs influence.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which the urinary tract and reproductive organs and related organs can be used by humans and animals. The Drug can be made using conventional intracorporeal modes of administration directly or indirectly in, or substantially in the vicinity of, tissues, which are treated, including those of the urethra, the Bladder, urethra, kidneys, vulva, vagina, cervix, the uterus, fallopian tubes, ovaries, penis, testes, vas deferens, prostate, epididymis and breast. Such modes of administration provide a direct delivery of the drug at, in or substantially near tissues that are being treated or systemic delivery of the drug, in or essentially nearby of tissues being treated ready.

example indications shut down a treatment for: Urinary tract disease, including cancerous and precancerous hyperplasia, Dysplasia and neoplasms, tumors or other growth, inflammation and Infection of the bladder, ureter, urethra and kidneys; cancerous and precancerous hyperplasia, Dysplasia and neoplasms, tumors and other growth, inflammation and Infection of the cervix, of the endometrium, the myometrium, the ovaries, the fallopian tube, the Uterus, the vulva and the vagina, including vagina warts; cancerous and precancerous hyperplasia, Dysplasia and neoplasms, tumors and other growth, inflammation and Infection of the prostate and testes; cancerous and precancerous hyperplasia, dysplasia and Neoplasms, tumors and other growth, inflammation and infection of the breast; metastatic tumors, such as metastases of melanoma, breast or other Tumors in tissues of the urinary tract and reproductive organs and related institutions; Reproductive organ infections, including tinea inguinalis, candidiasis, condyloma acuminatum, molluscum contagiosum, Herpes simplex genital infection, Lymphogranuloma venereum, Chankroid, Granuloma inguinale, Erythrasma; Psoriasis and lichen planus and lichen sclerosus. These examples be for illustrative purposes, since the present invention is not limited to the examples given and other indications, which the specialist knows, includes.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice and other animals which Tumors of different types have followed by irradiation of such tumors with X-rays, Gamma rays or other ionizing radiation, to a substantial or complete high-energy phototherapeutic destruction leads from such tumors. However, the present invention is not preferred to these embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as described herein, similar Uses for the specific indications described here and for various other similar ones Including indications those which are a therapeutic or cosmetic treatment of Urinary and reproductive organs and related organs of Humans and animals, and are within the present Invention included.

5. Procedure and medical use of the recipient's drug for high-energy phototherapeutic treatment of conditions affecting the respiratory tract and related organs influence.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which the respiratory tract and related organs of humans and Animals can be used, can be used. The drug can be under Use of conventional intracorporeal modes of administration directly or indirectly in, or essentially nearby of tissues to be treated, including those of the lungs and alveoli, the Bronchi, the trachea, hypopharynx, larynx, nasopharynx, tears-nasal passages, sinuses and nasal cavities, be administered. Such modes of administration represent a direct Delivery of the drug to, in or substantially in the vicinity of tissues, which are being treated, or systemic delivery of the drug at, in or substantially near tissues that are being treated be ready.

example indications shut down a treatment for: Hyperplasia, dysplasia and neoplasia, cancer, inflammation and Infection of the nasal cavity, the paranasal sinuses, the tear-nasal passages, the Eustachian tube, nasopharynx, hypopharynx, larynx, the trachea, bronchi, lungs and alveoli; and metastatic tumors, such as metastases of melanoma, breast or other tumors in tissues the respriation and related organs. These examples be for illustrative purposes, since the present invention is not limited to the examples given and other indications, which the specialist knows, includes.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice and other animals which Tumors of different types have followed by irradiation of such tumors with X-rays, Gamma rays or other ionizing radiation, to a substantial or complete high-energy phototherapeutic destruction leads from such tumors. However, the present invention is not preferred to these embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as described herein, similar Uses for the specific indications described here and for various other similar ones Including indications those requiring therapeutic treatment of the respiratory tract and of related organs of humans and animals, and are included within the present invention.

6. Procedures and medical use of the recipient's drug for high-energy phototherapeutic treatment of conditions affecting the circulatory system and related organs influence.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which the circulatory system and related organs of humans and Animals can be used, can be used. The drug can be under Use of conventional intracorporeal modes of administration directly or indirectly in, or essentially nearby of tissues being treated, including those of the heart that Kidneys, liver and blood vessels. Such Modes of administration provide a direct delivery of the drug at, in or substantially near tissues that are being treated or systemic delivery of the drug, in or essentially nearby of tissues being treated ready.

example indications shut down a treatment for: Hyperplasia, dysplasia and neoplasia, cancer, inflammation and Infection of the kidneys and liver; metastatic tumors, such as metastases of melanoma, breast or other tumors in tissues of the circulatory system and related organs; Disease of the heart and pericardium tissue and the circulatory tissues, including arteries and veins, including plaque and infections of such tissues as bacterial endocarditis; and the destruction of unwanted blood vessels, such as Spider veins. These examples are for illustrative purposes provided since the present invention is not indicated on the Examples restricted and other indications known to those skilled in the art.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice and other animals which Tumors of different types have followed by irradiation of such tumors with X-rays, Gamma rays or other ionizing radiation, to a substantial or complete high-energy phototherapeutic destruction leads from such tumors. However, the present invention is not preferred to these embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as described herein, similar Uses for the specific indications described here and for various other similar ones Including indications those who have a therapeutic treatment of the circulatory system and of related organs of humans and animals, and are included within the present invention.

7. Procedures and medical use of the recipient's drug for high-energy phototherapeutic treatment of conditions affecting the head and neck influence.

The inventors have discovered that the intracorporeal drugs disclosed herein in a very um in order to improve high-energy phototherapeutic treatment of various conditions affecting the head and neck of humans and animals can be used. The medicament can be administered directly or indirectly into or substantially in the vicinity of tissues being treated, including those of the head, neck, brain, eyes and ears, using conventional intracorporeal administration modes. Such modes of administration provide for direct delivery of the drug, in or substantially in the vicinity of tissues being treated, or systemic delivery of the drug, in or substantially in the vicinity of tissues being treated.

example indications shut down a treatment for: Tumors or resected tumor beds of intracranial and other Head and neck tumors; ophthalmic tumors and other diseases, including Macular degeneration and diabetic retinopathy; metastatic tumors, such as metastases of melanoma, breast or other tumors in tissues of the head or neck. These examples are for illustrative purposes provided since the present invention is not indicated on the Examples restricted and other indications known to those skilled in the art.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice containing tumors of different Types, such as radiation-resistant metastatic melanomas, followed by irradiation of such tumors with X-rays, gamma rays or other ionizing radiation, to an essential or complete high-energy phototherapeutic destruction of such tumors leads. The However, the present invention is not limited to this preferred embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as here described, similar Uses for the specific indications described here and for different ones other similar ones Including indications those which have a therapeutic or cosmetic treatment of the Head and neck of humans and animals affect, and are within of the present invention included.

8. Procedures and medical use of the first-time drug for high-energy phototherapeutic treatment of conditions affecting the endocrine and Iymphoreticular Affect systems and related organs.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which are the endocrine and lymphoreticular systems and related organs can be used by humans and animals. The Drug can be made using conventional intracorporeal modes of administration directly or indirectly in, or substantially in the vicinity of, tissues, which are treated, including those of the thyroid, the Thalamus and the hypothalamus, the pituitary gland, the lymph nodes and the lymphoreticular Systems, administered. Provide such modes of administration direct delivery of the drug, in or substantially near of tissues being treated or systemic delivery of the drug, in or substantially near tissues, which are treated, ready.

example indications shut down a treatment for: Hyperplasia, dysplasia and neoplasia, cancer, inflammation and Infection of the thyroid, of the thalamus and the hypothalamus, the pituitary gland, the lymph nodes and the lymphoreticular Systems, including Graves's disease; and metastatic tumors, such as metastases of melanoma, Breast or other tumors in tissues of the endocrine and lymphoreticular systems and related organs; These examples are for illustrative Purposes provided because the present invention is not limited to the given examples limited and other indications known to those skilled in the art.

In an example of a preferred embodiment of this method of treatment or medical use, the inventors have discovered that an intratumoral injection of a drug solution containing Rose Bengal at a concentration of about 1 to 10% w / v into mice and other animals containing tumors of various types Having such types followed by irradiation of such tumors with X-rays, gamma rays or other ionizing radiation results in substantial or complete high energy phototherapeutic destruction of such tumors. However, the present invention is not limited to this preferred embodiment, since other medicaments disclosed herein may also be used. Further, other formulations of the halogenated xanthenes have, as here , and similar uses for the particular indications described herein and for various other similar indications, including those relating to a therapeutic treatment of the endocrine and lymphoreticular systems and related organs of humans and animals, and are included within the present invention.

9. Procedures and medical use of the recipient's drug for high-energy phototherapeutic treatment of conditions, which various other Tissues such as connective tissue and various tissue surfaces which while a surgical procedure are exposed.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which different other internal and external tissues of humans and animals, such as connective tissue and various tissue surfaces, the while a surgical procedure are exposed, influence, used can be. The drug can be prepared using conventional intracorporeal modes of administration directly or indirectly in, or substantially near, tissues which be treated, including those of tissue surfaces, the while a surgical procedure, including one endoscopic surgical procedure or other endoscopic Procedure, administered. Provide such modes of administration direct delivery of the drug, in or substantially near of tissues being treated or systemic delivery of the drug, in or substantially near tissues, which are treated, ready.

example indications shut down a treatment for: arthritis, like those of arthritis; resected tumor beds of thoracic, abdominal or other tumors; metastatic tumors, such as metastases of breast tumors in the skin; Tumors or infections of the pleura, the peritoneum or the pericardium; metastatic tumors, such as metastases of melanoma, Breast or other Tumors in connective tissues and various tissue surfaces which while a surgical procedure are exposed; and several others essentially similar Indications. These examples are for illustrative purposes provided since the present invention is not indicated on the Examples restricted and other indications known to those skilled in the art.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an intratumoural injection of a drug solution administered by Rose Bengal in in a concentration of about 1 to 10% w / v, in mice and other animals which Tumors of different types have followed by irradiation of such tumors with X-rays, Gamma rays or other ionizing radiation, to a substantial or complete high-energy phototherapeutic destruction leads from such tumors. However, the present invention is not preferred to these embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as described herein, similar Uses for the specific indications described here and for various other similar ones Including indications those having a therapeutic or cosmetic treatment of states the various other tissues of humans and animals, such as connective tissue and various tissue surfaces, the while a surgical procedure are exposed, affect, affect and are included within the present invention.

10. Procedure and medical use of the recipient's drug for high-energy phototherapeutic treatment of conditions associated with microbial viral fungal or parasitic Infection are related.

The Inventors have discovered that the intracorporeal Medications in a very extensive way to improve one high-energy phototherapeutic treatment of various states which with microbial, viral, fungal or parasitic infection are related, can be used by humans and animals. The Drug can be made using conventional intracorporeal modes of administration directly or indirectly in, or substantially near, tissues which be treated, including those tissue surfaces, the while a surgical procedure, including one endoscopic surgical procedure or other endoscopic Procedure, administered. Provide such modes of administration direct delivery of the drug, in or substantially near of tissues being treated or systemic delivery of the Drug, in or substantially in the vicinity of tissues, which are treated be ready.

example indications shut down a treatment for: bacterial and antibiotic-resistant bacterial infection, including those which of Gram-positive and Gram-negative, Streptomycetes, Actinomycetes, Staphylococci, streptococci, Pseudomonas, Escherichia coli, mycobacteria and others are caused; Infection caused by filamentous fungi and not filamentous Fungi such as Cryptosporidium, Histoplasma, Aspergillus, Blastomyces, Candida and others are caused; parasitic infection caused by a Amoeba (including the Use when dissolving and kill an amoeba in amoebic Cysts), Trichinella, Dirodfilaria (Dirofilaria immitis in dogs) is caused, and various other substantially similar Indications. These examples are for illustrative purposes provided since the present invention is not indicated on the Examples restricted and other indications known to those skilled in the art.

In an example of a preferred embodiment of this treatment method or medical use, the inventors have discovered that an administration of an aqueous Solution, which Rose Bengal in a concentration of about 1 to 10 micromolar contains antibiotic-resistant Staphylococcus aureus, Escherichia coli, various other Gram-positive and Gram-negative bacteria and different yeasts in an accumulation of such Rose Bengal results in such organisms; with a subsequent irradiation to a substantial or complete destruction of such microbes leads. The However, the present invention is not limited to this preferred embodiment limited, since other medicines disclosed here can also be used. Further have other formulations of the halogenated xanthenes, as here described, similar Uses for the specific indications described here and for different ones other similar ones Including indications those having a therapeutic or cosmetic treatment of microbial, viral, fungal or parasitic Infection of humans and animals, and are within of the present invention included.

Table 1. Chemical and physical properties of some halogenated example xanthenes.

Table 2. Partition coefficients for several halogenated xanthenes; K _p is the ratio of the equilibrium concentrations of an agent in a lipophilic phase (n-octanol) which has been contacted with an aqueous phase (saline).

These Description was only for provided for illustrative purposes and it is not intended the invention of this application, which is covered by the claims below is defined to limit.

What as new and desirable is claimed to protect it by the patent is in the attached claims explained.

Claims (29)

A drug for intracorporeal administration, wherein the medicament comprises at least one halogenated xanthene as one primary Active ingredient in aqueous solution wherein the halogenated xanthene in a concentration of higher than 0.001% and less than 20% is present and taking the drug for use in high-energy phototherapeutic treatment of human and animal tissue, using of applied ionizing radiation with an energy of more as 1 KeV and less than 1000 MeV. The medicament of claim 1, wherein the halogenated Xanthen includes at least one compound selected from the group those from fluorescein; 4 ', 5'-dichlorofluorescein; 2 ', 7'-dichlorofluorescein; 4,5,6,7-tetrachloro; 2 ', 4', 5 ', 7'-tetrachlorofluorescein; Dibromofluorescein; Solvent Red 72; Diiodfluorescein; ethyleosin; Erythrosine B; Phloxin B; Rose Bengal; 4,5,6,7-Tetrabromoerythrosin; Mono-, di- or tribromerythrosine; Mono-, di- or trichloroerythrosine; Mono-, di- or trifluoroerythrosine; 2 ', 7'-dichloro-4,5,6,7-tetrafluorfluorescein; 2 ', 4,5,6,7,7'-Hexafluorfluorescein and 4,5,6,7-tetrafluorofluorescein consists. The medicament according to claim 2, wherein the halogenated Xanthen Rose Bengal includes. The medicament according to claim 2, wherein the halogenated Xanthene 4,5,6,7-tetrabromerythrosine. The medicament according to any preceding claim, further comprising at least one coupled to the halogenated xanthene Receiver unit. The medicament according to claim 5, wherein the receptor unit selected from the group which consists of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), Amino acids, Proteins, antibodies, Ligands, haptens, carbohydrate receptors, carbohydrate complexing agents, Lipid receptors, lipid complexing agents, protein receptors, Protein-complexing agents Chelating agents, encapsulating vehicles, short chain aliphatic Hydrocarbons, long-chain aliphatic hydrocarbons, aromatic hydrocarbons, aldehydes, ketones, alcohols, Esters, amides, amines, nitriles, azides, hydrophilic units and hydrophobic units. The medicament according to any preceding claim, wherein the halogenated xanthene is present in a delivery vehicle, which includes an additive selected from the group which from builders, Stabilizers, emulsifying agents, dispersants, preservatives, Buffers, electrolytes, tissue penetrating agents and tissues softening agents. The medicament according to any preceding claim, wherein the medicament is useful for the treatment of indications, which is selected from the group are, from states, which affect the skin and related organs, conditions that affect the mouth and digestive tract and related organs, states the urinary and reproductive organs and related organs affect states, which affect the respiratory tract and related organs, states that affect the circulatory system and related organs, states that affect the head and neck, the conditions affecting the endocrine and lymphoreticular Affect systems and related organs, conditions that affect connective tissue, states the tissue surfaces affect that during a surgical procedure are exposed, and conditions that are related to microbial, viral, fungal and parasitic infections, consists. The medicament according to any preceding claim, wherein the ionizing radiation is applied X-radiation. The medicament according to any one of claims 1 to 8, wherein the ionizing radiation is applied gamma radiation. The medicament of any preceding claim, wherein said intracorporeal administration comprises a route of administration selected from the group consisting of: intravenous injection, intraperitoneal injection, intramuscular injection, intracranial injection, intratumoral injection, intraepithelial injection, transcutaneous delivery, esophageal administration, intra-abdominal administration, intra-apendicular administration, intra-arterial administration, intra-articular administration, intrabronchial administration, intrabuccal administration, intracapsular administration, intracardiac administration, intra-cartilaginous administration, intracavitary administration, intra-cephalic administration, intracranial Administration, intradermal administration, intracystic administration, intradermal administration, intraductal administration, intraduodenal administration, intrarafascicular administration, intrafertilar administration, intrafibrillar administration, intrafissural administration, intragastric administration, intraglandular administration, intrahepatic administration, intraintestinal administration, intralamellar administration, intralesional administration, intraligamentous administration, intralingual Administration, breast administration, intramedullary administration, intrameningeal administration, intramyocardial administration, intranasal administration, intraocular administration, intraoperative administration, intraoral administration, intraosseous administration, ovarian administration, pancreatic administration, intraparietal administration, intrapelvic administration, intrapericardial administration, intraperineal administration monitoring, intraperitoneal administration, placental administration, intrapleural administration, intrapontine administration, prostate administration, intrapulmonary administration, spinal administration, intrarectal administration, intrarenal administration, intraskleral administration, intrascrotal administration, intrasegmental administration, intrasellar administration, intraspinal administration, Spleen administration, intrasternal administration, intrastromal administration, intrasynovial administration, intratarsal administration, intratesticular administration, intrathoracic administration, intratonsillar administration, intratracheal administration, intratubal administration, intratympanic administration, intraureteric administration, intraurethral administration, uterine administration, intravaginal administration, intravascular Administration, intraventricular administration, intravertebral administration, intravesi administration and intravitrous administration. Use of a halogenated xanthene in the Preparation of an aqueous intracorporeal drug for high-energy phototherapeutic treatment of disorders, which is selected from the group are those who are cancerous and precancerous Hyperplasia, dysplasia and neoplasia, benign epithelial tumors, malignant Epithelial tumors, resected tumor beds, benign proliferative disorders, malignant proliferative disorders, Vascular plaque, inflammation and infection of human or animal tissue, wherein the halogenated xanthene in a concentration higher than 0.001% to less than 20% and applied ionizing radiation used with an energy of more than 1 KeV and less than 1000 MeV becomes. The use according to claim 12, wherein the intracorporeal Drug includes a drug that is effective when it is in or near of human or animal tissue, and wherein the phototherapeutic treatment irradiating the halogenated Xanthens with the applied ionizing radiation. The use according to at least one halogenated Xanthene according to claim 12 or claim 13 in the manufacture of an intracorporeal medicament, which is effective against a disease caused by the application of ionizing radiation, wherein the halogenated xanthene is activated will, can be treated. The use according to any one of claims 12 to 14 for the manufacture of a medicament for the treatment of disorders, the skin, the mouth and the digestive tract, the urinary tract and Reproductive organs, the respiratory tract, the circulatory system, the head and neck, the endocrine and lymphoreticular systems, Connective tissue, tissue surfaces, the while of a surgical procedure are exposed, and microbial, viral, fungal and parasitic infections. The use according to any one of claims 12 to 15, wherein the halogenated xanthen comprises Rose Bengal. The use according to any one of claims 12 to 15, wherein the halogenated xanthene comprises 4,5,6,7-tetrabromerythrosine. The use according to any one of claims 12 to 17, wherein the ionizing radiation applied ionizing radiation is, the X-rays is. The use according to any one of claims 12 to 17, wherein the ionizing radiation applied ionizing radiation is that's gamma radiation. The use of any one of claims 12 to 19, wherein the intracorporeal drug is formulated for administration by a route selected from the group consisting of intravenous injection, intraperitoneal injection, intramuscular injection, intracranial injection, intratumoral injection, intravenous epithelial injection, transcutaneous delivery, esophageal administration, intra-abdominal administration, intra-apendicular administration, intra-arterial administration, intra-articular administration, intra-bronchial administration, intrabuccal administration, intracapsular administration, intracardiac administration, intra-cartilaginous administration, intracavitary administration, intra-cephalic administration, intracranial administration, intracutaneous administration, intra-cystic administration, intradermal administration, intraductal administration, intraduodenal administration, intrafascicular administration, intra-fetal administration, intrafibrillar administration, intrafissural administration, intragastric administration, intraglandular administration, intrahepatic administration, intraintestinal administration, intralamellar administration, intralesional administration, intraligamentous administration, intralingual administration, administration chest, intramedullary, intranasal, intramyocardial, intranasal, intraocular, intraoperative, intraoral, intraosseous, ovarian, pancreatic, intraparietal, intrapelvic, intrapericardial, intraperineal , intraperitoneal administration, placental administration, intrapleural administration, intrapontine administration, prostate administration, intrapulmonary administration, spinal administration, intrarectal administration, intrarenal administration, intraskleral administration, intrascrotal administration, intrasegmental administration, intrasellar administration, intraspinal administration, administration spleen, intrasternal administration, intrastromal administration, intrasynovial administration hunger, intratarsal administration, intratesticular administration, intrathoracic administration, intratonsillar administration, intratracheal administration, intratubal administration, intratympanic administration, intraureteric administration, intraurethral administration, uterine administration, intravaginal administration, intravascular administration, intraventricular administration, intravertebral administration, intravesical administration, and intravitrotic Administration exists. A medicine for intracorporeal administration, comprising a halogenated xanthene in aqueous solution, wherein the halogenated Xanthene in a concentration higher than 0.001% and lower is present as 20% and the composition for use in high-energy Phototherapeutic treatment using applied Ionizing radiation with an energy of more than 1 KeV and less is suitable as 1000 MeV. A pharmaceutical composition according to claim 21, wherein the composition for obtaining a high energy phototherapeutic effect via donning adapted to an effective amount of applied ionizing radiation is. The pharmaceutical composition according to claim 21 or claim 22, wherein the halogenated xanthene includes at least one compound which selected from the group is made of fluorescein; 4 ', 5'-dichlorofluorescein; 2 ', 7'-dichlorofluorescein; 4,5,6,7-tetrachloro; 2 ', 4', 5 ', 7'-tetrachlorofluorescein; Dibromofluorescein; Solvent Red 72; Diiodfluorescein; ethyleosin; Erythrosine B; Phloxin B; Rose Bengal; 4,5,6,7-Tetrabromoerythrosin; Mono, di-tribromerythrosine; Mono-, di- or trichloroerythrosine; Mono-, di- or trifluoroerythrosine; 2 ', 7'-dichloro-4,5,6,7-tetrafluorfluorescein; 2 ', 4,5,6,7,7'-hexafluorofluorescein and 4,5,6,7-tetrafluorofluorescein. The pharmaceutical composition of claim 23, wherein the halogenated Xanthen Rose Bengal includes. The pharmaceutical composition of claim 23, wherein the halogenated Xanthene 4,5,6,7-tetrabromerythrosine. The medicament according to any one of claims 21 to 25, further comprising at least one of the halogenated xanthene coupled receiver unit. The pharmaceutical composition according to claim 26, wherein the receptor unit selected from the group which consists of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), Amino acids, Proteins, antibodies, Ligands, haptens, carbohydrate receptors, carbohydrate complexing agents, Lipid receptors, Lipid complexing agents, protein receptors, protein complexing agents, Chelating agents, encapsulating vehicles, short chain aliphatic Hydrocarbons, long-chain aliphatic hydrocarbons, aromatic hydrocarbons, aldehydes, ketones, alcohols, Esters, amides, amines, nitriles, azides, hydrophilic units and hydrophobic units. The medicament according to any one of claims 21 to 27, wherein the applied ionizing radiation is X-radiation. The medicament according to any one of claims 21 to 27, wherein the applied ionizing radiation is gamma radiation.